The present invention relates to spirocyclic piperidine compounds and to the preparation thereof. The spirocyclic piperidine compounds of the present invention are useful as intermediates in the synthesis of therapeutic agents. In particular the spirocyclic piperidine compounds of the present invention are useful as intermediates in the synthesis of certain neurokinin-1 (NK-1) receptor antagonists.
Compounds of formula (A) below, which are described in a number of published patent specifications (WO 97/49710, WO 98/13369, WO 98/49170 and WO 98/54187), are potent and selective NK-1 receptor antagonists. 
wherein
Ar represents a group selected from: 
R1 represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra or OSO2Ra, where Ra and Rb each independently represent hydrogen, C1-4alkyl or fluoroC1-4alkyl;
R1a represents halogen, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkoxyC1-4alkyl, fluoroC1-6alkyl, fluoroC1-6alkoxy, fluoroC1-6alkylthio, fluoroC1-6alkoxyC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C2-6alkenyloxy, cyano, phenoxy, benzyloxy, NRaRb, SRa, SORa, SO2Ra, or OSO2Ra, where Ra and Rb each independently represent hydrogen, C1-4alkyl or fluoroC1-4alkyl;
R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
or when R2 is adjacent to R1 or R1a, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two oxygen atoms;
R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR14, NRaSO2R14, or C1-4alkyl substituted by cyano or CO2Ra where Ra and Rb are as previously defined;
or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, xe2x80x94(CH2)rNRaRb, xe2x80x94(CH2)rNRaCORb, xe2x80x94(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or C1-4alkyl and r is zero, 1 or 2;
R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, CF3 or C1-6alkoxy substituted by C1-4alkoxy;
R6 represents hydrogen, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR12, CONR13C2-6alkenyl, CONR13C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
or R6 represents a group of the formula xe2x80x94CH2Cxe2x89xa1CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by xe2x95x90O or xe2x95x90S and optionally substituted by a group of the formula ZNR7R8 where
Z is C1-6alkylene or C3-6cycloalkyl;
R7 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 and R10 each independently represent hydrogen, halogen, C1-6alkyl, CH2ORe, oxo, CO2Ra or CONRaRb where Ra and Rb are as previously defined and Re represents hydrogen, C1-6alkyl or phenyl;
R12 represents ORa, CONRaRb or heteroaryl;
R13 represents hydrogen or C1-6alkyl;
R14 represents C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl; and
p is zero or 1;
and pharmaceutically acceptable salts thereof.
The aforementioned patent specifications describe the synthesis of compounds of formula (A) by a variety of methods. In particular, two useful intermediates are compounds of formula (B) and (C) 
Synthetic routes for the preparation of these compounds are described in the following reaction schemes: 
Another useful intermediate in the synthesis of compounds of formula (A) are compounds of formula (D). 
Compounds of formula (D) may be prepared, for example, by conversion of a stannane of formula (C) to the corresponding iodide by treatment with iodine at reduced temperature, for example, at about xe2x88x9278xc2x0 C., in a suitable solvent such as dichloromethane. The iodine may then be displaced to give the compound of formula (D) by treatment with, for example, xcex1,xcex1xe2x80x2-azo-isobutyronitrile and tributyltin hydride in a suitable solvent, for example, toluene, at an elevated temperature, for example, at about 100xc2x0 C.
Alternatively, compounds of formula (D) may be prepared by the cyclisation of a compound of formula (E) 
using suitable dehydrating reagents, for example, methanesulfonyl chloride or benzenesulfonyl chloride in pyridine or triethylamine in an organic solvent such as dichloromethane, or using triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.
The preferred compounds of formula (A) are reported to have a 5R, 6S stereochemistry, for example, as shown in formula (F) 
Thus, for instance, International Patent Specification No. WO 97/49710 (cross-referring also to European Patent Publication No. 0 528 495-A) describes the synthesis of (5R, 6S)-6-phenyl-1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4,5]dec-3-ene in an eight step synthesis from methyl 4-nitrobutyrate and benzaldehyde (Scheme D): 
We have now found a high yielding process for the rapid, stereocontrolled synthesis of functionalised spirocyclic piperidine compounds useful as intermediates in the synthesis of compounds such as those described in the aforementioned International Patent Specifications. The process utilises a multiple ring-closing metathesis (RCM) reaction to form the spirocycle, with relative stereochemistry being directed by the choice of substituent on the nitrogen atom. The reaction occurs under mild conditions and is tolerant of a wide range of functional groups. The products are amenable to further selective transformations.
A particular advantage of the process of the present invention is the fact that the process comprises significantly fewer reaction steps, compared with the conventional eight step reaction sequence. This short synthetic sequence is therefore more efficient for large scale synthesis, and affords less opportunity for unwanted side-reactions.
Another advantage of the process of the present invention is that both stereoisomers are accessible in a stereocontrolled manner. According to the conventional methodology, optically pure intermediates were obtained by resolution techniques, resulting in the production of a considerable amount of undesired isomer as a waste by-product.
The product of the multiple ring-closing metathesis reaction is amenable to further reaction in a stereocontrolled and regiocontrolled fashion. In this way pharmacologically interesting compounds such as those described in the aforementioned International Patent Specifications can be synthesised in a highly convergent and efficient way.
Thus, in a first aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) 
wherein Ts is a tosylate group and R is an alkyl group, an unsubstituted phenyl or substituted phenyl ring, or a benzyl or substituted benzyl group; which comprises:
(i) cyclising a compound of formula (II) 
in the presence of a suitable catalyst; and
(ii) purifying and collecting the resultant compound of formula (I).
In the compounds of formulae (I) and (II), R is preferably straight or branched C1-4alkyl, benzyl, phenyl or substituted phenyl. Where R is substituted phenyl, the phenyl ring is preferably substituted with 1 or 2 substituents as defined for R4 and R5 above.
Most preferably, R represents unsubstituted phenyl or 4-fluorophenyl.
Where R represents a substituted benzyl group, suitable substituents on the phenyl ring of the benzyl group include those defined for R4 and R5 above.
Suitable catalysts of use in step (i) of the present invention include any catalyst or multicomponent catalyst system that initiates olefin metathesis. Preferred catalysts are single component metal carbene complexes. Particularly preferred catalysts include: 
An especially preferred catalyst of use in the present invention is RuCl2(PCy3)2xe2x95x90CHPh, also referred to as Grubbs catalyst. These catalysts and their use is described, for instance, in the following literature:
Bazan et al., J. Am. Chem. Soc., 1991, 113, 6899 and references cited therein.
Nguyen et al., J. Am. Chem. Soc., 1992, 114, 3974.
Nguyan and Grubbs, J. Organomet. Chem., 1995, 497, 195.
Schwab et al., Angew. Chem. Int. Ed. Eng., 1995, 34, 2039.
Schwab et al., J. Am. Chem. Soc., 1996, 118, 100.
Grubbs and Chang, Tetrahedron, 1998, 54, 4413.
Suitable organic solvents of use in step (i) of the present invention include halogenated hydrocarbons, such as dichloromethane or chloroform.
Step (i) of the present invention is conveniently effected at room temperature and pressure, for example at about 20xc2x0 C.
Purification of the compound of formula (I) according to step (ii) of the present invention is required to remove the minor fraction of undesired stereoisomer. Purification is conveniently effected using column chromatography, although other conventional techniques known to one of ordinary skill in the art may be used.
Compounds of formula (II) may be prepared by reaction of a compound of formula (III) 
with an allyl halide, especially allyl bromide, in the presence of sodium hydride in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (THF/DMPU). The reaction is conveniently effected at room temperature and pressure, for example, at about 20xc2x0 C.
Compounds of formula (III) may be prepared by reaction of a compound of formula (IV) 
wherein Alk is a C1-4alkyl residue of the ester moiety, especially methyl, with a Grignard reagent, such as vinylmagnesium bromide, in the presence of cerium chloride. The reaction is conveniently effected in an aprotic solvent such as ether, for example tetrahydrofuran, at a reduced temperature, for example at about 0xc2x0 C.
Compounds of formula (IV) may be prepared by reaction of an amino acid ester of formula (V) 
or a salt thereof, preferably the hydrochloride salt thereof, with tosyl chloride in the presence of a suitable organic base, for example, triethylamine. The reaction is conveniently effected in an aprotic solvent such as an ether, for example, tetrahydrofuran, at room temperature and pressure, for example at about 20xc2x0 C.
Compounds of formula (I) are novel compounds and represent a further aspect of the present invention.
It will be appreciated that compounds of formula (A) above, and precursors therefor may be prepared in a conventional manner from the compounds of formula (I). Thus, for example, a reductive Heck reaction using a suitable halogenated aryl or heteroaryl compound (preferably where the halogen is iodine) may be used to introduce the ring Ar, or a precursor therefor. The reductive Heck reaction may be effected using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
The C9-C10 double bond may be removed by conventional hydrogenolysis and likewise the tosylate group removed using techniques well known to the person of ordinary skill in the art.
As stated above, the present invention provides a rapid stereocontrolled synthesis of functionalised spirocyclic piperidine compounds, the relative stereochemistry being directed by the choice of substituent on the nitrogen atom.
Thus, whilst the 5S, 6S compounds of formula (A) are less preferred than their 5R, 6S isomers, such compounds may nevertheless be useful pharmacological agents. The present invention therefore provides an efficient synthetic route to enable the preparation of the 5S, 6S isomers.
Thus, according to another aspect of the present invention, there is provided a process for the preparation of a compound of formula (VI) 
wherein Bn is a benzyl group and R is as previously defined; which comprises:
(i) cyclising a compound of formula (VII) 
in the presence of a suitable catalyst; and
(ii) purifying and collecting the resultant compound of formula (VI).
For the avoidance of doubt, the aforementioned preferences for the group R apply mutatis mutandis to the compounds of formulae (VI) and (VII).
Similarly, the aforementioned catalysts are suitable for use in step (i) of this aspect of the present invention, Grubbs catalyst being preferred.
Suitable organic solvents of use in step (i) of this aspect of the present invention include halogenated hydrocarbons, such as dichloromethane or chloroform. The cyclisation is conveniently effected at room temperature and pressure, for example at about 20xc2x0 C.
Purification of the compound of formula (VI) according to step (ii) of this aspect of the present invention is required to remove the minor fraction of undesired stereoisomer. Purification is conveniently effected using column chromatography, although other conventional techniques known to one of ordinary skill in the art may be used.
Compounds of formula (VII) may be prepared by reaction of a compound of formula (VIII) 
with an allyl halide, especially allyl bromide, in the presence of sodium hydride in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (THF/DMPU). The reaction is conveniently effected at room temperature and pressure, for example, at about 20xc2x0 C.
Compounds of formula (VIII) may be prepared by reaction of a compound of formula (IX) 
with a Grignard reagent, such as vinylmagnesium bromide, in the presence of cerium chloride. The reaction is conveniently effected in an aprotic solvent such as ether, for example tetrahydrofuran, at a reduced temperature, for example at about 0xc2x0 C.
Compounds of formula (IX) may be prepared by reaction of a compound of formula (X) 
or a salt thereof, preferably the hydrochloride salt thereof, with an allyl halide, especially allyl bromide, in the presence of a suitable organic base, for example, diisopropylamine. The reaction is conveniently effected in a solvent such as dimethylformamide, at an elevated temperature, for example at about 60xc2x0 C.
Compounds of formula (X) are readily prepared from the corresponding primary amine by conventional N-benzylation techniques, for example, reaction of the amino acid with benzaldehyde in the presence of a sodium hydroxide, followed by treatment with sodium borohydride.
Compounds of formula (VI) are novel compounds and represent a further aspect of the present invention.
According to a further aspect of the present invention, there is provided a method for the synthesis of the spirocyclic piperidinyl compounds described in International Patent Publication Nos. WO 97/49710, WO 98/13369, WO 98/49170 or WO 98/54187. Alternatively, there is provided a method for the synthesis of compounds of formula (A) as described herein. Said method comprises the double ring closing metathesis reactions described and claimed herein, followed by one or more synthetic steps to complete the synthesis of the desired compound. Suitable methods for completing the synthesis are described in the aforementioned International Patent Publications.
In particular, the use of the double ring closing metathesis reactions described and claimed herein in the preparation of the spirocyclic piperidinyl compounds disclosed in WO 97/49710 is preferred. Especially preferred compounds described in WO 97/49710 include:
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(difluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
(3R, 5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-(4-fluorophenyl)-1-oxa-7-aza-spiro[4,5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
and pharmaceutically acceptable salts thereof.
Thus, according to a further preferred aspect of the present invention there is provided a process for the preparation of a compound of formula (XVII): 
wherein Ar is a phenyl or 4-fluorophenyl group; and
R3xe2x80x2 is a trifluoromethyl, trifluoromethoxy or difluoromethoxy group; or a pharmaceutically acceptable salt thereof which comprises:
(i) cyclising a compound of formula (XI) 
in the presence of a suitable catalyst;
(ii) reacting the resultant compound of formula (XII) with a compound of formula (XIII) 
wherein PG is a hydroxy-protecting group, in particular, a benzyl group, and LG is a leaving group such as triflate (xe2x80x94OSO2CF3) or a halogen atom, for example, chlorine, bromine or iodine, in particular, iodine, under reductive Heck conditions using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide or triethylamine, and a reducing agent, preferably lithium chloride and potassium hydrogencarbonate, or formic acid or a salt thereof, such as potassium formate;
(iii) deprotecting and hydrogenating the resultant compound of formula (XIV) 
(iv) reacting the resultant phenol of formula (XV) 
with (1-iodo-cycloprop-1-yl)phenylsulfide in the presence of silver carbonate;
(v) reacting the resultant compound of formula (XVI) 
according to either
(a) reaction with lithium naphthalenide in a suitable solvent such as an ether, for example, tetrahydrofuran, the reaction being effected at reduced temperature, for example at about xe2x88x9278xc2x0 C.; or
(b) in a first step, oxidation of the phenylthio moiety using, for example, oxone in the presence of aluminium oxide, the reaction being effected in a suitable solvent such as a halogenated hydrocarbon, for example, chloroform, and conveniently at room temperature, and in a second step, removal of the phenylsulfonyl moiety using, for example, sodium amalgam in the presence of disodium hydrogen orthophosphate, the reaction being effected in a suitable solvent such as an alcohol, for example, methanol, and at a reduced temperature, for example, between 0xc2x0 C. and 10xc2x0 C.
(vi) purifying and collecting the resultant compound of formula (XVII) 
and optionally, said process being followed, where necessary, by the removal of the tosyl protecting group where present;
and/or, if desired, converting the resulting compound or a salt thereof, into a pharmaceutically acceptable salt thereof.
In particular, the compound of formula (XVII) is selected from:
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(difluoromethoxy)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-(4-fluorophenyl)-1-oxa-7-aza-spiro[4,5]decane; and
(3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane;
or a pharmaceutically acceptable salt thereof.
Suitable catalysts of use in step (i) of this aspect of the present invention are as previously described, Grubbs catalyst being preferred.
Suitable organic solvents of use in step (i) of this aspect of the present invention include halogenated hydrocarbons, such as dichloromethane or chloroform. The cyclisation is conveniently effected at room temperature and pressure, for example at about 20xc2x0 C.
Suitable hydrogenation conditions of use in step (iii) of this aspect of the present invention include catalytic hydrogenation in the presence of a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as an alcohol, for example, methanol, an ester, for example, ethyl acetate, or an organic acid, for example, acetic acid, or a mixture thereof.
Step (v) of this aspect of the present invention is preferably effected at a reduced temperature, for example, at about xe2x88x9278xc2x0 C.
Suitable pharmaceutically acceptable salts of the compounds of formula (XVII) include acid addition salts which may, for example, be formed by mixing a solution of the compound of formula (XVII) with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.